The etiology and pathogenesis of Interstitial Cystitis (IC) are unknown. One current theory proposes that there may be alterations in bladder neurotransmitters, and another suggests a decrease in bladder blood flow which may be responsible for the symptoms and bladder changes see in IC. Preliminary data from the examination of bladder biopsies from patients with IC suggests that there may be a deficiency in nitric oxide synthase in the bladder of these patients. Our hypothesis is that alterations in the nitric oxide pathway, either a deficiency or dysfunction, leads to a reduction in blood flow in at least one subgroup of patients with IC, and produces the characteristic clinical picture. The studies to be described are designed to test the hypothesis that alterations in nitric oxide and/or nitric oxide synthase, either qualitatively or quantitatively, lead to a reduction in bladder blood flow which results in the clinical and histologic changes observed in interstitial cystitis. The first studies investigate the localization of nitric oxide in the bladder, and its role in the regulation of bladder blood flow. The second phase compares the content and activity of nitric oxide synthase in the bladder of IC patients as compared to normal controls. The third set of experiments compare the bladder blood flow of IC patients with that of normal controls, both in the resting basal state, and changes in blood flow with filling and emptying. The final studies investigate whether bladder ischemia can produce changes in voiding behavior and histological changes as observed in interstitial cystitis. Together these studies will establish the role of nitric oxide in bladder blood flow, determine whether there is a deficiency or decrease in function of the nitric oxide pathway in IC patients vs. controls, determine whether IC patients have a lower baseline bladder blood flow or impaired response to filling and emptying than controls, and finally determine whether reductions in bladder blood flow can produce the changes in voiding pattern and histology observed in IC. These findings taken together would support our initial hypothesis.